Microgranules containing cisplatin

Details Microgranules containing cisplatin Microgranules containing cisplatin

1999-09-08

2002-10-01

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S493000, C424S494000, C424S497000

Reexamination Certificate

active

06458389

ABSTRACT:

The present invention relates to a cisplatin formulation for oral administration.
Cisplatin is an anticancer agent known for its effectiveness but also for its significant side effects observed when it is administered intravenously, in particular: nephrotoxicity, gastrointestinal toxicity (nausea, vomiting), neurotoxicity and moderate myelo-suppression.
The nephrotoxicity induced by cisplatin can be alleviated by intravenous saline hydration and by diuresis.
For the last twenty-five years, research has been carried out on cisplatin analogues. Only twelve of these analogues have been evaluated in clinical trials: some have proved to be even more toxic than cisplatin and none has shown an anticancer activity superior to cisplatin.
Researchers have thus turned towards the study of the reduction in toxicity of cisplatin rather than towards that of new analogues.
A first line of research relates to the oral administration of cisplatin in animals.
Studies carried out by Siddik Z. H. et al. and presented at the 74th Congress of the American Cancer Research Association in March 1984 allowed the anticancer activity of cisplatin administered by the oral route in mice affected by plasmacytoma ADJ/PLA to be evaluated. The plasma platinum concentration reached a peak of 4.3 &mgr;g/ml after 30-60 minutes for a dose of 50 mg/kg. The bioavailability in the mouse was 31-36% and the incidence of nephrotoxicity was only 20%.
Hasegawa Y. et al. confirm with respect to Muridae, in Chem. Pharm. Bull., 33(12), 5511-5514, 1985, that cisplatin passes into the blood after oral administration and that it is effective under these conditions against solid tumours.
Binks S. P. et al. demonstrate, in Biochemical Society Transactions, 616th Meeting, London, 14, 694 (1986), that the absorption of cisplatin after oral administration is so rapid that the plasma platinum concentration reaches its maximum in less than two hours. The highest levels of platinum are observed in the kidneys.
Analysis with an electron microscope of tissues excised 48 hours after oral administration of cisplatin reveals only slight changes in the kidneys, whereas, for an intravenous administration, symptoms of nephrotoxicity are observable.
Borch R. F. et al. have shown, in Proc. Natl. Acad. Sci., USA, 76, 6611-6614, that urea concentrations in the blood were multiplied by 14 in rats receiving the maximum tolerated dose of cisplatin via the intravenous route and then this result was confirmed by another study by Morgan S. E. et al. (Pharmacology Communication, 1993, Vol. 3, No. 1, 9-18) and shows that administration by the oral route can greatly decrease the nephrotoxicity of cisplatin. No histopathological change in the kidneys was observed in mice treated orally with a toxic dose of cisplatin of 70 mg/kg.
Howell S. B., in Plenum Press, New York. p. 93 (1991), and Harrap K. R. et al., in Adv. Enzyme Regul., 31 (31), 1991, show that the degree of activity of cisplatin administered by the oral route is less than that obtained by the parenteral route and that higher doses are necessary for an oral administration because of the relatively low bioavailability of cisplatin in this case. Consequently, no clinical trial has been carried out on man because the bioavailability of cisplatin administered by the oral route was too low in comparison with conventional intravenous formulations.
A second line of research relates to the combination of low doses of cisplatin with other therapeutic methods.
T. Shirasaka has provided, in Cancer Chemother. Pharmacol., 32, 167-172 (1993) and in Jpn. J. Cancer Chemother., 2/(7), 1025-1028 (1994), a therapy which consists in combining the administration of 5-fluorouracil and low-dose cisplatin. He suggests a therapy of four weeks, which consists in administering a perfusion of 5-fluorouracil in combination with an intravenous dose of 5-6 mg/day of cisplatin.
The anticancer effectiveness of this therapy on the solid tumours of the rodents studied is superior to that of 5-fluorouracil alone or of cisplatin alone and its toxicity is lower.
Many studies carried out in Japan have shown that, with a low-dose regimen, cisplatin in combination with 5-fluorouracil is effective in the treatment of various cancers; moreover, its toxicity is reduced. It is then no longer necessary to resort to hydration by an intravenous route in order to prevent nephrotoxicity.
Moreover, it has been demonstrated, in Chemotherapy, 1996, Vol/Iss/Pg 42/6 (452-458), that low-dose cisplatin can also be combined with S
1
, an antitumour medicament of oral form which is a tegafur/5-chloro-2,4-dihydroxypyridine/oxonic acid mixture in a 1/0.4/1 molar proportion discovered by T. Shirasaka.
Other combinations of low-dose cisplatin are also possible with other anticancers, such as, but not restricted to, the combination of vinblastine with bleomycin, the combination of etoposide with bleomycin, or alternatively paclitaxel.
In addition, Ducreux M. et al., in Annals of Oncology, 5 (Suppl 8), 81 (1994), have shown that the combination of radiotherapy and of an administration of 4-6 mg/m
2
/day of cisplatin by the intravenous route for 4-6 weeks improves the anticancer activity and reduces the side effects.
There currently exists no oral cisplatin formulation and the object of the present invention is to provide controlled-release microgranules for oral administration containing cisplatin, the mean particle size of which is between 0.4 and 1.5 mm, in particular between 1 and 1.25 mm.
Controlled release is understood to mean an instantaneous release, a release sustained over time or alternatively a release with targeting of the absorption site, in particular at the ileum where the pH is of the order of 7.
This formulation advantageously provides a bioavailability superior to that of cisplatin of injectable form administered orally and an acceptable gastrointestinal toxicity.
After an intravenous administration, the plasma platinum concentration increases and then decreases rapidly, which leads to significant fluctuations in concentration and causes periods of therapeutic under-and over-concentration responsible for nephrotoxicity and nausea/vomiting.
The controlled-release microgranules formulation according to the invention advantageously makes it possible to release the active principle more evenly and to avoid plasma peaks while maintaining a blood level which is sufficiently high to produce the desired therapeutic effect, without, however, reaching toxic levels which can cause side effects for the patient, because of the extensive distribution of the granules along the digestive tract.
The formulation according to the invention also makes it possible to keep the plasma concentration constant over a longer period of time and to decrease the variations between and within individuals by virtue of a high exchange surface area and avoids the release of a large amount of active principle localized at one point of the digestive mucous membrane.
An advantage of the oral form according to the invention is that it can be used by the patient himself in his home; thus, the patient no longer has to resort to frequent intravenous administrations in a hospital which require professional assistance. Moreover, for hospitalized patients, the oral form according to the invention improves the quality of life by reducing the time spent in hospital and by freeing them from painful treatments, in particular in the case of perfusions at the rate of 100 hours/week.
Each microgranule according to the invention advantageously comprises an immediate microgranule to which is fixed a coating containing a coating agent which makes possible the controlled release of cisplatin and/or of other active principles, the said immediate microgranule being composed either of a mixture of excipients, of cisplatin and optionally of other active principles or of a neutral support grain coated with a mixture of excipients, of cisplatin and optionally of other active is principles.
Immediate microgranule is understood to mean a microgranule, the formulation excipients of which have no signific

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